Typhoid Toxin and Salmonella Typhi pathogenesis

伤寒毒素和伤寒沙门氏菌发病机制

基本信息

批准号：
10686399
负责人：
Jorge E Galan
金额：
$ 57.7万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686399
关键词：
ADP Ribose Transferases Acute Animal Experiments Animal Model Applications Grants Bacteria Bacterial Proteins Biology Cell model Cells Central Nervous System Cessation of life Clinical DNA Damage Deoxyribonucleases Developing Countries Development Disease Disease Outbreaks Engineering Exhibits Extracellular Space Family member Food Poisoning Foundations Funding Gastroenteritis Grant Health Human Infection Intoxication Knowledge Label Laboratories Lethargies Life Link Membrane Glycoproteins Metabolic Mus Pathogenesis Pathogenicity Pathway interactions Phenotype Predisposition Prevention strategy Protein Secretion Proteins Proteomics Public Health Recording of previous events Salmonella Salmonella enterica Salmonella paratyphi Salmonella typhi Salmonella typhimurium Stupor Symptoms Therapeutic Tissues Toxin Transferase Typhoid Fever United States Vaccines Vacuole base combat fascinate genetic makeup human pathogen human tissue improved insight novel novel therapeutics pathogen prevent public health relevance receptor vesicle transport

项目摘要

PROJECT DESCRIPTION Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~200,000 deaths every year. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause limited gastroenteritis, S. Typhi is an exclusive human pathogen and causes systemic, often lethal, disease. Despite its Public Health importance, the mechanisms of pathogenesis of typhoidal Salmonellae remain poorly understood. Our laboratory has been exploring the unique aspects of S. Typhi pathogenesis and devoted a substantial amount of effort to the study of typhoid toxin, an A2B5 toxin that is highly conserved in typhoidal Salmonella serovars (i. e. S. Typhi and S. Paratyphi), but that it is largely absent from non-typhoidal Salmonellae. Typhoid toxin is an atypical AB toxin in that, unlike all known AB5 toxin family members, it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) with an as of yet unidentified host target, and a deoxyribonuclease (CdtB), which inflicts DNA damage on intoxicated cells. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. Typhoid toxin is uniquely adapted to humans as it recognizes Neu5Ac-terminated sialoglycans on surface glycoproteins. Administration of typhoid toxin to experimental animals can reproduce many of the acute pathognomonic symptoms of typhoid fever, including stupor and lethargy, which most likely involve the central nervous system (CNS). Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellular bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole and subsequently transported to the extracellular space by specific vesicle transport carriers. During the past funding period we have unraveled many mechanistic aspects of the biology of typhoid toxin, including the description of its unique mechanism of intracellular expression, the characterization of all the steps of its remarkable transport pathways, the discovery of novel bacterial protein secretion mechanism, the description of its unique evolutionary history, and the discovery of an alternative form of typhoid toxin. Finally, these studies have led to the discovery of a novel cell-intrinsic pathogen restriction mechanism that prevents the replication of S. Typhi in mouse tissues and that it is antagonized by the mouse pathogen S. Typhimurium through the activity of specific type III protein secretion effectors absent from S. Typhi. These studies have raised very important questions related to pathogenesis of typhoid fever that we intend to pursue during the next funding period.

项目描述肠沙门氏菌伤寒血清型（伤寒沙门氏菌）和相关血清型副伤寒沙门氏菌引起伤寒人类，这是一种毁灭性的疾病，每年导致约 20 万人死亡。虽然大多数情况都会发生在发展中国家，美国偶尔也会爆发疫情。与其他肠道沙门氏菌不同伤寒沙门氏菌是一种独特的血清型，可感染多种宿主并可引起有限的胃肠炎。人类病原体并导致全身性疾病，通常是致命的疾病。尽管其对公共卫生具有重要意义，伤寒沙门氏菌的发病机制仍知之甚少。我们的实验室已探索伤寒沙门氏菌发病机制的独特方面，并投入大量精力进行研究伤寒毒素是一种 A2B5 毒素，在伤寒沙门氏菌血清型（即伤寒沙门氏菌和伤寒沙门氏菌）中高度保守。副伤寒沙门氏菌），但非伤寒沙门氏菌基本上不存在。伤寒毒素是一种非典型AB毒素与所有已知的 AB5 毒素家族成员不同，它具有两个酶活性亚基：ADP 核糖基转移酶 (PltA) 具有尚未识别的宿主靶标，以及脱氧核糖核酸酶 (CdtB)，它会造成 DNA 对中毒细胞的损害。这两个亚基彼此共价连接并与一个由 PltB 组成的同源五聚体 B 亚基。伤寒毒素独特地适应人类，因为它识别表面糖蛋白上的 Neu5Ac 末端唾液酸聚糖。伤寒毒素对实验动物的施用动物可以重现伤寒的许多急性症状，包括昏迷和昏迷。嗜睡，这很可能涉及中枢神经系统（CNS）。伤寒毒素表现出显着的生物学的特点是它仅由细胞内细菌产生，在合成和组装后释放进入含有沙门氏菌的液泡，随后通过特定的转运到细胞外空间囊泡运输载体。在过去的资助期间，我们解开了该项目的许多机制方面的问题。伤寒毒素的生物学，包括其独特的细胞内表达机制的描述，其非凡运输途径的所有步骤的表征，新型细菌蛋白质的发现分泌机制、其独特进化历史的描述以及替代品的发现伤寒毒素的形式。最后，这些研究发现了一种新型细胞内在病原体阻止伤寒沙门氏菌在小鼠组织中复制的限制机制，并且它被小鼠病原体鼠伤寒沙门氏菌通过缺乏特定的 III 型蛋白分泌效应子的活性来自伤寒沙门氏菌。这些研究提出了与伤寒发病机制相关的非常重要的问题，我们打算在下一个资助期内继续进行。